Efeito do metabólito de bupivacaína, pipecolil xilidida, na asma experimental refratária a glicocorticoides

Abstract

Local anesthetics, including bupivacaine, act as such via their capacity to block sodium channels. However, they are also known for their ability to provide alternative beneficial clinical effects at concentrations far below those required for sodium channel blockade. We studied the effect of nebulized bupivacaine and its non-anesthetic metabolite pipecolyl xylidide (PPX) on allergen-induced asthma changes in mice. Bupivacaine and PPX (1-2%, nebulized) were administered immediately after the ovalbumin challenge, and dexamethasone (3 mg / kg, orally) was administered 1 hour before ovalbumin challenge in sensitized A/J mice. Airway hyperreactivity, total and differential leukocytes in bronchoalveolar lavage fluid, peribronchial eosinophil density, interleukin (IL)-4, IL-13, eotaxin-1 and KC, epithelial mucus and extracellular-matrix deposition were evaluated. The impact of treatments on DO11.10 T cell survival and proliferative responses was assessed in vitro. Anesthetic and safety properties were assessed in vivo. We found that following four daily intranasal allergen challenges, A/J mice reacted with robust Airway hyper-reactivity, leukocyte infiltration, mucus exacerbation, peribronchial fibrosis and increased levels of IL-4, IL-13, KC and eotaxin-1. All these changes being clearly sensitive to PPX. In contrast, these changes remained unaltered after bupivacaine or dexamethasone treatment, except for the accumulation of eosinophil in the BAL fluid. Both bupivacaine and PPX (10-1000 μM) inhibited in a concentration-dependent manner T cell survival and proliferative response following exposure to allergen in vitro. Furthermore, while the local anesthetic activity of PPX was drastically reduced in comparison to bupivacaine, both lethality (in mice) and hemodynamic changes (in rats) were clearly more pronounced in those animals treated with bupivacaine as compared to those treated with PPX. Our findings show that nebulized PPX, but not bupivacaine, inhibits pivotal features of asthma in a murine model expressing a certain degree of refractoriness to glucocorticoids. These effects were likely due to down-regulation of pro-inflammatory cytokines and chemokines and subsequent blockade of eosinophilic infiltration in the lung tissue.